Phosphoramides



United States Patent PHOSPHORAMIDES Charles H. Tilford and Frederick J. McCarty, Cincinnati,

and Marcus G. Van Campen, Jr., Wyoming, Ohio, assignors to The Wm. S. Merrell Company, Cincinnati, Ohio, a corporation of Delaware No Drawing. Application February 27, 1956 Serial No. 567,735

2 Claims. (Cl. 260294.7)

This invention relates to new chemical compounds which are useful as depressants for the central nervous system.

The new compounds can be represented by the generic formula in which S signifies that the ring is saturated; n is an integer from 1 to 4 inclusive; R is selected from the group consisting of the hydrogen atom and the methyl and ethyl radicals; R and R are selected from the group consisting of the methyl, ethyl, phenyl, chlorophenyl, tolyl, methoxyphenyl, benzyl, phenetyl, and cyclohexyl radicals; and R and R are lower alkoxy radicals having from 1 to 8 carbon atoms. The radical represented by the formula can be attached to the piperidine ring at the 2-, 3- or 4- position.

The new phosphoramides are prepared by the reaction of a dialkylchlorophosphate with piperidinemethanols such as those disclosed in U. S. Patent 2,624,739 to Werner and Tilford; in our copending application, Serial No. 462,122, filed October 13, 1954; in copending application Serial No. 478,506, filed December 29, 1954, of Edward L. Schumann, Marcus G. Van Campen, Jr. and Raymond C. Pogge; and in copending applications Serial No. 487,464, filed February 10, 1955, and Serial No. 515,803, filed June 16, 1955, of Charles H. Tilford, Frederick J. McCarty, Marcus G. Van Campen, Jr., and Raymond C. Pogge. These intermediates produce compounds of the above generic formula in which R and R are selected from the group consisting of the hydrogen atom and the lower alkyl, e. g. isobutyl, lower alkylphenyl, lower alkoxyphenyl, hydroxyphenyl, halophenyl, aminophenyl, dimethylaminophenyl, methylenedioxyphenyl, ptrimethylsilylphenyl, mesityl, naphthyl, methoxynaphthyl, bicyclo (2.2.l)-2-heptyl, 3 to 8 carbon-atom ring cycloalkyl, lower alkylcyclohexyl, phenylcyclohexyl, methylisopropylcyclopentyl, furyl, tetrahydrofuryl, thienyl, pyridyl, piperidyl and indolyl radicals, and R and R when taken together with the carbon atom to which they are attached represent substituents selected from the group consisting of the bornyl, fenchyl, l-indanyl, l-tetralyl, 9-fluorenyl, 9-xanthyl, 10-thioxanthyl, 9-anthryl and 9- acridyl radicals and the like.

The new compounds, in general, affect the central nervous system by depression. The usefulness of these compounds in many cases, however, lies in the variations in mood which they produce rather than in measurable depression, e. g., some of the compounds cause dogs to 2 become very amenable to command and people less bothered by worries and external annoyances. The new compounds are insoluble and thus advantageously are administered orally in tablet or other suitable form. Oral doses of the compounds of the invention should be in the 10 to milligram range for human use.

The preparation of the piperidinemethanols from which the compounds of this invention are derived is illustrated below by Examples I to V. Examples VI to XVI illustrate the reaction of piperidinemethanols with a dialkylchlorophosphate to produce the phosphoramides of the present invention. These procedures are applicable to the preparation of all of the new compounds and are not to be construed as limiting the scope of the invention.

EXAMPLE I a,a-DiphertyI-Z-piperidinemethanol A mixture of 48 grams (0.167 mole) of a,a-diphenyl-2- pyridinemethanol hydrochloride (Emmert et al., Ber. 72B, 1188 [1939]; 74B, 714 [1940]), ml. of ethanol, and 0.5 gram of Adams platinum catalyst was shaken under an initial hydrogen pressure of 60 lbs. The theoretical amount of hydrogen was absorbed in 5 hours. The reaction mixture was refluxed, diluted with enough Water to dissolve all of the white solid which formed, and filtered hot from the catalyst. The filtrate was cooled and filtered; yielding a white product melting at 308-309 C. with decomposition.

Analysis-Calculated for C H 0N-HCl: Cl, 11.75. Found: Cl, 11.85.

EXAMPLE I1 a-Phenyl-a-methyI-Z-piperidinemethanol hydrochloride was absorbed in 1 hour. The mixture was filtered and the filtrate was evaporated on the steam bath. The residue was recrystallized from butanone. The white crystalline hydrochloride product had a melting point of 182-184 C.

EXAMPLE III raga-Diphenyl-6-methyl-2-piperidinemethanol Ethyl-6-methy1picolinate not hitherto reported in the literature was prepared by refluxing a mixture of 100 grams (0.66 mole) of 6-methyl-picolinic acid, grams of ethanol, and 167 grams of concentrated sulfuric acid for 4 hours. The reaction mixture was subjected to vacuum distillation on the steam bath to remove most of the unchanged ethanol and the residue was treated with 200 ml. of concentrated ammonium hydroxide. The oil that formed was extracted with benzene and fractionally distilled; boiling point 122126 C. at 10 mm; 21 1.5060.

Analysis.Calcd. for C H O N: C, 65.45; H, 6.71. Found: C, 65.28; H, 6.61.

u,a-Diphenyl-6-methyl-Z-pyridinemethanol was prepared (according to the procedure of Example IV of copending application of Tilford et al., Serial No. 462,122, filed October 13, 1954), using 11 grams (1.6 moles) of lithium, 126 grams (0.80 mole) of bromobenzene and 64 grams (0.39 mole) of the above ethyl-6-methylpicolinate. To the lithium in dry ether is added the br0mobenzene in dry ether with refluxing. To the cooled mixture is then added the ethyI-G-methylpicolinate. A crude product melting at 6474 C. was obtained which, after being recrystallized from methanol, had ,a melting {min of 8891 C.

Analysis.-Calcd. for C H ON: C, 82.90; H, 6.23. Found: C, 82.71, H, 6.32.

The hydrochloride salt melted at 171-176 C. when recrystallized from methanol ether.

Analysis.-Calcd. for C H ON-HCI: C, 73.19; H, 5.82. Found: C, 73.18; H, 5.98.

Hydrogenation of the above hydrochloride was carried out (by the procedure of Example I of copending application, Serial No. 462,122, filed October 13, 1954) to give the desired piperidinemethanol-HCI which melted at 278279 C. with decomposition.

A-nalysz's.Calcd. for C H ON-HCl: C, 71.78; H, 7.61. Found: C, 71.83; H, 7.59.

EXAMPLE IV a,u-Diphenyl-3-piperidinemethanol A mixture of 25 g. (0.084 mole) of u,a-diphenyl-3- pyridinemethanol-HCI [H. E. French, I. Am. Chem. Soc. 73, 469 (1951), reported M. P. 150-155 C. (chars). This preparation: M. P. 227-232 C.] 200 ml. of methanol, and 0.6 g. of platinum oxide catalyst was hydrogenated according to the procedure of Example I. A yield of 20 g. of product melting at 184-186 C. (decomposition) was obtained.

The product was recrystallized from methanol-ether; yield: (a) 10 g. (39%); M. P. 203-205 C. (decomposition) and (b) 7 g. (28%); M. P. 182-184 C. An analytical sample of (a) melted at 206-208" C., (b) at 184-186 C. The melting point of an equal mixture of (a) and (b) was, 184-188 C. The product evidently exists in two polymorphic crystalline forms.

Analysis.--Calcd. for C H ON-HCI: C, 71.15; H, 7.30. (a) Found: C, 71.35; H, 7.57. (b) Found: C, 71.11;H, 7.52.

EXAMPLE v a,a-Di-p-tlyl-4-piperidinemethanol Method D, disclosed in application, Serial No. 462,122, filed October 13, 1954, and described in Example III above, was used to prepare a,a-di-p-tolyl 4-pyridinemethanol which was obtained in 34 percent yield and had a melting point of 154-156 C. The pyridinemethanol hydrochloride melted at 202-203 C. The piperidinemethanol was obtained from the pyridinernethanol hydrochloride by hydrogenation and had a melting point of 188- 190" C.

Other piperidinemethanols, which are useful in the preparation of the new compounds include:

a-Methyl-u-ethyI-Z-piperidinemethanol u,a-Diethyl-6-methyl-2-piperidinemethanol e,a-Diphenyl-4,6-dimethyl-2-piperidinemethan01 a-Phenyl-a-(p-tolyl -4-ethyl-2-piperidinemethanol a Phenyl a (p methoxyphenyl) 6 methyl 2 piperidinemethanol a,a:-Dio-methoxyphenyl) -2- pip eridineme thanol a-(6-Tolyl)-a-(p-methoxyphenyD-Z-piperidinemethanol a-Methyl-a-ethyl-3-piperidinemethanol apt-Di (m-methoxyphenyl -3-piperidinemethanol a,a-Di(p-tolyl)-4,6-dimethyl-3-piperidinemethanol a (p-Tolyl) -vz- (o-methoxyphenyl) -3 -piperidinemethanol a,u-Diphenyl-6-ethyl-3-piperidinemethanol e,a-DiphenyI-Z,6-dimethyl-4-piperidinemethanol u,a-Di(o-methoxyphenyl -6-ethyl-4-piperidinemethanol u,a-Dimethyl-6-ethyl-4-piperidinemethanol a,Methyl-a-ethyl-4-piperidinemethanol EXAMPLE VI N-dz'ethylphosphoryl-a,a-diphenyl-2-piperidinemethanol To 12.7 g. (0.047 mole) of 0c,ot-dlPhCXlYl-Z-PiPfilidillE- methanol in 100 ml. of benzene was added 4.6 ml. (0.025 mole) of diethylchlorophosphate. The mixture was refiuxed six hours and allowed to stand for 48 hours at room 4 temperature. The mixture was filtered and a precipitate of 6.7 g. was obtained as the HCl salt.

The filtrate, containing the crude N-diethylphosphoryla,a-diphenyl-Z-piperidinemethanol, was evaporated on the steam bath and the residue extracted with 100 ml. of ether under reflux. The ether extract was diluted with an equal volume of petroleum ether, cooled and filtered. The precipitate of the crude N-diethylphosphoryl-a,ot-diphenyl- 2-piperidinemethanol was recrystallized from ether; M. P. 162-165 C.

Analysis-Called. for C H O NP: N, 3.47; P, 7.68. Found: N, 3.61; P. 7.68.

This compound is useful as a depressant for the nervous system in the above-indicated dosages.

EXAMPLE VII N -diethylphosphoryl-a,a-diphenyl-4-piperidinemethan0l Following the procedure of Example VI using aux-diphenyl-4-piperidinemethanol (prepared from u,a-diphenyl- 4-pyridinemethanol following the procedure of Example I), 60 percent of the desired product was obtained; M. P. 223-224 C.

Analysis.Calcd. for C 'H O NP: N, 3.47; P, 7.68. Found: N, 3.68; P, 7.35.

This compound is useful as a depressant for the nervous system in the above-indicated dosages.

EXAMPLE VHI N-diethylphosphoryl-u-cyclohexyl-ot-phenyZ-4-piperidinemethanol ot-Cyclohexyl-a-phenyl-4-pyridinemethanol was prepared as follows. A solution of g. (0.3 mole) of 4- benzoylpyridine in 100 ml. of toluene was added at 20 to an ether solution of cyclohexylmagnesiurn chloride prepared from g. (0.5 mole) of cyclohexyl chloride, 13 g. (0.54 mole) of magnesium turnings and 250 ml. of dry ether. The mixture was then refluxed an hour, decomposed with aqueous ammonium chloride and filtered; yield: 52 g. of crude base melting at 184-186". An analytical sample melted at 193-194".

Analysis.-Calcd. for 0,,H,,0N= C, 80.83; H, 7.92. Found: C, 80.60; H, 7.80. I

The hydrochloride salt melted at 205-207 dec.

Analysis.- Calcd. for C H 0N-HCl: C, 71.17; H, 7.30. Found: C, :97; H, 7.28.

a-Cyclohexyl-a-phenyl-4-piperidinemethanol was pre pared by the hydrogenation of 16 g. (0.052 mole) of the above hydrochloride in 100 ml. of ethanol with 0.8 g. of platinum oxide catalyst. The reaction mixture was filtered, the filtrate evaporated on the steam bath to a volume of 60 ml. and diluted with 4 volumes of dry ether. The solution was cooled and filtered; yield: 16 g. (98%) of desired hydrochloride melting at 279-280 dec. An analytical sample melted at 280-281 dec.

Analysis-ceded. for CmHzqONHCIZ C, 69.75; H, 9.11. Found: C, 69.42; H, 9.10.

The desired N-diethylphosphoryl derivative was prepared as follows. A mixture of 23 g. (0.073 mole) of the above piperidine hydrochloride and 16.5 g. (0.163 mole) of triethylamine in 300 ml. of dry benzene was refluxed an hour with stirring. To this mixture was added 14.3 g. (0.084 mole) of diethyl chlorophosphate over a period of an hour at 4050. The reaction mixture was refluxed 16 hours, and then filtered from the solid triethylamine-HCL The filtrate was washed with water and evaporated on the steam bath to a volume of about 100 ml. About 300 ml. of 40-60" petroleum ether was added, the mixture cooled and filtered; yield: 20 g. of crude product. A second crop obtained by evaporation and dilution with pet. ether amounted to 8.7 g. The two .crops were recrystallized from 80% methanol to give 18.5 -g. (62%) of desired N -diethylphosphoryl-a-cyclohexyl-a-phenyl-4-piperidinemethanol melting at 113-114".

Analysis.--Calcd. for C H O NP: N, 3.42; P, 7.56. Found: N, 3.32; P, 7.60.

This compound is useful in the medical management of such psychotic and psychoneurotic conditions as hallucinations, delusions and psychotic and psychoneurotic over-activity, e. g., the improvement and suppression of symptoms of dementia praecox (schizophrenia), hallucinations of alcoholism, and the manic manifestations of manic depressive psychoses, in the above-indicated dosages. The compound is also useful as a depressant for the nervous system.

EXAMPLE IX N-diethylphosphoryl-a-(p-anisyl) -u-phenyl-4-piperidinemethanol Analysis.Calcd. for c,,H,,o,N-Hc1: c, 68.35; H,

7.25. Found: C, 67.99; H, 7.39.

This piperidine hydrochloride was converted to the desired diethylphosphoryl derivative using 14 grams (0.042 mole) and following the procedure in Example VIII. The N-diethylphosphoryl-a-(p-anisyl)-a-pheny1-4- piperidinemethanol was obtained in 48% yield and had a melting point of 143145 C.

Analysis.Calcd. for C H O NP: N, 3.23; P, 7.15. Found: N, 3.24; P, 7.08.

This compound is useful as a depressant for the nervous system in the above-indicated dosages.

EXAMPLE X N -diethylphosph oryl-a-(o-tolyl -u-phenyl-4-piperidinemethanol u'o-Tolyl-a-phenyl-4-pyridinemethanol 'was prepared from 90 g. (0.49 mole) of 4-benzoylpyridine in 200 ml. of toluene and o-tolyllithium obtained from 7 g. (1 gram atom) of lithium, 86 g. (0.5 mole) of o-bromotoluene, and 380 ml. of dry ether (following directions in Example VIII for a-cyclohexyl-a-phenyl-4-pyridinemethanol); yield: 102 g. (75%); M. P. 229231 fusing.

Analysis.Calcd, for C I-I ON: C, 82.89; H, 6.23. Found: C, 82.02; H, 6.36.

The hydrochloride melted at 2l4215 dec.

Analysis,-Calcd. for C H ON-HCl: C, 73.19; H, 5.82. Found: C, 72.96; H, 5.86.

The, hydrochloride (36 g.; 0.115 mole) was hydrogenated in 230 ml. of ethanol containing 1 g. of platinum catalyst. The desired a-(o-tolyl)-u-phenyl-4-piperidinemethanol'HCl obtained amounted to 22 g. (61%) M. P.

256257 dec. I

Analysis.-Calcd. for C H ON-HCl: C, 71.79; H, 7.61. Found: C, 71.43; H, 7.47.

This piperidine hydrochloride was converted to the desired diethylphosphoryl derivative following the procedure in Example VIII. The N-diethylphosphoryl-a-otolyl-a-phenyl-4-piperidinemethanol melted at 179-181". Analysis.Calcd. for C H O NP: N, 3.36; P, 7.42. Found: N, 3.38; P, 7.58. I

This compound is useful as a depressant for the nervous system in the above-indicated dosages.

of dry benzene was carried out.

6 EXAMPLE XI N-diethylphosphoryl-a,a-di-(o-tolyl)-4-piperidinemethanol The intermediate u,x-di-(o-tolyl)-4-pyridinemethanol was obtained as follows. To o-tolyllithium prepared from 148 g. (0.86 mole) of o-bromotoluene, 12 g. (1.7 mole) of lithium and 600 ml. of dry ether was added 50 g. (0.33 mole) of ethyl isonicotinate at -20 over a period of 30 minutes. The mixture was then refluxed an hour, decomposed with aqueous ammonium chloride, and filtered. The white precipitate was recrystallized from 1.8 liters of 75% ethanol; yield: 78 g. (82%); M. P. 178- 182. An analytical sample obtained by recrystallization from -90 pet. ether melted at 185186.

AnalysiS.-CalCd. for C H ON: C, 83.00; H, 6.62. Found: C, 82.72; H, 6.46.

The hydrochloride salt melted at 208-210 dec.

Analysis.Calcd. for C H ON-HCl: C, 73.72; H,

6.19. Found: C, 73.72; H, 6.26.

Hydrogenation of 40 g. (0.12 mole) of the above hydrochloride gave 18 g. (45%) of desired 0t,0L-dl-(O-IO1Y1)- 4-piperidinemethanol-HC1 melting at 305306 dec.

Analysis.Calcd. for C H ON-HCl: C, 72.40; H, 7.90. Found: C, 72.27;H, 8.02.

This hydrochloride was converted to the desired N-diethylphosphoryl oc,o1. di (o tolyl) 4 piperidinemethanol, which melted at 128-130 using the procedure of Example VIII.

Analysis.Calcd. for C H O NP: N, 3.25;,P, 7.18. Found: N, 3.30; P, 7.09.

This compound is useful as a depressant for the nervous system in the above-indicated dosages.

EXAMPLE XII N-dibutylph0sph0ryl-a,u-diphenyl-4-piperia'inemethanol The procedure in Example VIII was carried out using 14 g. (0.046 mole) of a,a-dipheny1-4-piperidinemethanol- HCl, 11.4 g. (0.05 mole) of dibutyl chlorophosphate and 210 ml. of dry benzene, and 15 g. of crude product melting at about 15916 3 was obtained. Recrystallization from methanol gave 12 g. (58%) of desired N-dibutylphosphoryl compound melting at 162163.

Analysis.-Calcd. for C H O NP: N, 3.05; P, 6.74. Found: N, 3.23; P, 6.61.

This compound is useful as a depressant for the nervous system in the above-indicated dosages.

EXAMPLE XIII v N -di0cty lphosphoryl-a,a-diphcnyl-4 pi peridinemethanol The procedure of Example VIII using 14 g. (0.046 mole) of a,a.-diphenyl-4-piperidinemethanol-HC1, 18.4 g. (0.05 mole) of dioctyl chlorophosphate and 250 ml. The desired product was crystallized from ethyl acetate; yield 4.6 gm. (17.5%), M. P. 65-80 C.; M. P. 89-91 C. when pure.

This compound is useful as a depressant for the nervous system in the above-indicated dosages.

EXAMPLE XIV The intermediate a-(p-chlorophenyl)-u-phenyl-4-pyridinemethanol was prepared as follows:

To the Grignard reagent prepared from 21 g. (0.86 g. atom) of magnesium turnings, 172 g. (0.90 mole) of p-chlorooromoben'zene and 500 ml. of dry ether was added g. (0.60 mole) of '4-benzoyl pyridine in ml. of dry ether at '-20 C. over a one hour period with stirring. The mixture was allowed to warm up to 25 C. and refluxed on a'steam bath for a 1 to 2 hour period. It was then decomposed with 90 g. (1.5 moles) of acetic acid in 100 ml. of water and filtered to give g. 0f crude material. A 30 g. sample of the crudematerial was recrystallized from ethanol to give 16 g. (54%) of product melting at 202-204 C.

Analysis.-Calcd. for C H ONCl: C, 73.09; H. 4.77. Found: C, 73.10; H, 4.83.

a-(p-Chlorophenyl)-u-phenyl-4-piperidinemethanol was prepared by treating a mixture of 16 g. (0.054 mole) of the above free base in 250 ml. of absolute ethanol with 4.5 ml. (0.054 mole) of alcoholic hydrogen chloride; 0.5 g. of platinum oxide was added and the mixture was shaken in the presence of hydrogen (initial pressure of 60 lbs.) until the theoretical amount of hydrogen was absorbed. The product crystallized during the hydrogenation and was dissolved by adding a large quantity of absolute ethanol and heating. The catalyst was removed by filtration and the filtrate was cooled and filtered; yield 9 g. (50%); M. P. 256259 C. An analytical sample melted at 263-264 C.

Anolys'is.-Calcd. for C H ONCl-HCl: C. 63.90; H, 6.26. Found: C, 63.80; H, 6.36.

This piperidine hydrochloride was converted to the desired diethylphosphoryl derivative following the procedure of Example VIII. The N-diethylphosphowl-a-(pchlorophenyl)-a-phenyl-4-piperidinemethanol melted at 150-151 C.

Analysis.-Calcd. for C H O NPCl: N, 3.20; P, 7.08. Found: N, 3.28; P, 6.95.

This compound is useful as a depressant for the nervous system in the above-indicated dosages.

EXAMPLE XV N-diethylphosphoryl-a-(p-phenetyl) -mphenyl-4-piperidinemeZhanol The intermediate a-(p-phenetyl)-ot-phenyl-4-pyridinemethanol was prepared as follows:

-To 6.94 g. (1.00 g. atom) of lithium in 750 ml. of dry ether was added 100.5 g. (0.50 mole) of p-bromophenetole in 100 ml. of dry ether over a /2-hour period with refluxing. The solution was cooled to 60 C. and an ether solution of 86 g. (0.47 mole) of 4-benzoylpyridine was added over a fifteen minute period. The reaction mixture was stirred for 3 hours and allowed to rise to C. and then decomposed with ammonium chloride solution. The crude product was removed by filtration and washed with water to give 100 g. (70% yield) of free base, M. P. l77-184 C. An analytical sample melted at 187-189" C. A crystalline hydrochloride was not obtained.

Analysis.Calcd. for C H O N: C, 78.65; H. 6.27. Found: C. 78.71; H, 6.38.

w(p-Phenetyl)-a-phenyl-4-piperidinemethanol was prepared by adding a solution of g. (0.146 mole) of oily hydrochloride from above in 250 ml. of methanol to 0.8 g. of platinum oxide. The mixture was shaken in the presence of hydrogen (initial pressure of lbs.)

until the theoretical amount of hydrogen was absorbed. The mixture was filtered and the filtrate cooled and crystallized to give 17 g. (34%) melting at l79-l8l C. An analytical sample melted at 198-199 C.

Analysis.-Calcd. for C I-I O N-HCl: C, 69.06; H, 7.54. Found: C, 69.17; H, 7.67.

This piperidine hydrochloride was converted to the desired diethylphosphoryl derivative following the procedure of Example VIH. The N-CIICihYlPhOSPlIOI'Yl-a- (p-phenetyl)-ot-phenyl-4-piperidinemethanol melted at 149-151" C.

Analysis.-Calcd. for C H O NP: N, 3.13; P, 6.92. Found: N, 3.12; P, 6.90.

EXAMPLE XVI N-diethylphosphoryl-u-benzyl-m-phenyl-4- piperidinemethanol From 4-benzoylpyridine and beniylmagnesium chloride, the intermediate a-benzyl-a-phenyl-4-pyridinemetha- 8 I101 was prepared using the procedure of Example XIV and was obtained in 47% yield. The product melted at 188-189 C.

AnaZys'is.-Calcd. for C19H17ONI C, 82.92; H, 6.23. Found: C, 82.86; H, 6.29.

The hydrochloride salt melted at 267-269 C.

Analysis.Calcd. for C H oN-HClr C, 73.21; H, 5.82. Found: C, 73.40; H, 5.82.

Hydrogenation of 46 g. (0.167 mole) of the above hydrochloride gave 39 g. (75%) of desired piperidinemethanol. HCl melting at 250-252 C. (decomposition).

Analysis.Calcd. for C H ON-HCk C, 71.81; H, 7.61. Found: C, 72.02; H, 7.66.

This piperidine hydrochloride was converted to the desired diethylphosphoryl derivative following the procedure of Example VIII. The N-diethylphosphoryl-ubenzyl-a-phenyll-piperidinemethanol melted at 109- 112 C.

Analysis.-Calcd. for C H O NP: N, 3.36; P, 7.42. Found: N, 3.29; P, 7.21.

This compound is useful as a depressant for the nervous system in the above-indicated dosages.

Other N-dialkyl phosphoryl-piperidinemethanols of this invention which are prepared by the above procedures include:

N dimethylphosphoryl a phenyl a methyl 2- piperidinemethanol.

N di n propylphosphoryl oz phenyl a ethyl- Z- iperidinemethanol.

N di n butylphosphoryl ct,a diphenyl 6 methyl- 2-piperidinemethanol.

N di n hexylphosphoryl a,a di(p-tolyl) 6- ethyl-2-piperidinemethanol.

N di n octylphosphoryl 0:,0: di(o methoxyphenyl) -2-piperidinemethanol.

N di i propylphosphoryl oc,a dimethyl 2- piperidinemethanol.

N ethyl t butylphosphoryl 0:,0: diethyl 2- piperidinemethanol.

N methyl i amylphosphoryl 0t,oc diphenyl 2- piperidinemethanol.

N ethyl sec butylphosphoryl 05,0: diphenyl 2- piperidinemethanol.

N dimethylphosphoryl a phenyl cc methyl 3- piperidinemethanol.

N diethylphosphoryl a phenyl a ethyl 3- piperidinemethanol.

N di i propylphosphoryl ,Ot diphenyl 6 methyl-S-piperidinemethanol.

N di n hexylphosphoryl 0:,0: di(p-t0lyl) 3- piperidinemethanol.

N di n octylphosphoryl u,a di(o methoxyphenyl) -3-piperidinemethanol.

N dimethylphosphoryl 08,02 diphenyl 4 piperidinemethanol.

N diethylphosphoryl u,a diphenyl 4 piperidinemethanol.

N di n butylphosphoryl 02,0: di(o tolyl) 4- piperidinemethanol.

N di n hexylphosphoryl ct,ot diethyl 4 piperidinemethanol.

N di n octylphosphoryl a phenyl a ethyl 4- piperidinemethanol.

N di n butylphosphoryl on, diphenyl 2,6 dimethyl 4 piperidinemethanol.

We claim:

1. The compounds of the formula P O RlRt 9 in which S signifies that the ring is saturated; n is an integer from 1 to 4 inclusive; R is selected from the group consisting of the hydrogen atom and the methyl and ethyl radicals; R and R are selected from the group consisting of the methyl, ethyl, phenyl, chlorophenyl, tolyl, methoxy phenyl, benzyl, phenetyl, and cyclohexyl radicals; and

10 R and R are lower alkoxy radicals having from 1 to 8 carbon atoms.

2. N diethylphosphoryl a cyclohexyl on phenyl- 4-piperidinemethanol.

No references cited.

UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,832,7 86 April 29, 1958 Charles H. Tilford et 21.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 3, line 58, for a-(6-To1y1)-a-(p-methoxyphenyl)-2-piperidinemethanol read u-(p-To1yl)-a-(p-methoxyphenyl) -2-p1peridinemethan01-; column 4:, line 2, after 6.7 g. insert the following of a,a-diphenyl-2- piperidinemethano1; line 47, for G, 70:97 read C, 70.97; column 7, line 19, for C, 63.80 read -O, 6882-.

Signed and sealed this 19th day of August 1958.

Attest: KARL H. AXLINE, ROBERT C. WATSON, Attestz'ng Oyfioer. Commissioner of Patents. 

1. THE COMPOUNDS OF THE FORMULA 